Elias A D, Antman K H
Cancer Treat Rep. 1986 Jul;70(7):827-33.
The regimen of doxorubicin (DOX), ifosfamide (IFF), and dacarbazine (DTIC) (AID) for previously untreated inoperable or metastatic sarcoma has acceptable toxicity with significant activity. Twenty patients received 79 courses of DOX (60-75 mg/m2) with or without DTIC (900 mg/m2) by continuous infusion over 72 hours with escalating doses of IFF and mesna uroprotection. Nineteen patients were evaluable for toxicity. Myelosuppression was dose-limiting. The maximum tolerated dose was DOX at 60 mg/m2, DTIC at 900 mg/m2, and IFF at 7500 mg/m2 per course. Of the 79 courses analyzed, 33 (42%) resulted in wbc counts less than 1000/microliter; 14 (18%) were complicated by fever and neutropenia, and three by sepsis. There were no toxic deaths. Relative platelet sparing was observed and nadirs were brief. In contrast to bolus-dose DTIC divided over 5 days, DTIC by continuous infusion did not add significantly to gastrointestinal toxicity. Nausea and vomiting was well controlled by antiemetics. Mucositis occurred sporadically. Unlike our phase II study of IFF alone, no CNS or renal toxicity was observed. No cardiac toxicity was encountered, although only four patients have received greater than 450 mg/m2 of cumulative DOX. One episode of DOX extravasation occurred despite a long iv line that extended to the axilla. No serious tissue damage was observed, perhaps due to the dilute solutions of DOX used. Partial responses were seen in eight of 18 evaluable patients (44%) and in six of 11 patients at or near the phase II level. Two additional patients with minimal response have continued tumor regression. The median number of courses before partial response was four (range, one to five). The median duration of response has not been reached (3+ to 10+ months). An inoperable primary has been rendered surgically resectable in one patient. Activity in previously untreated sarcomas should be further evaluated in a randomized phase III study against a standard DOX-containing combination.
对于先前未经治疗的无法手术切除或转移性肉瘤，阿霉素（DOX）、异环磷酰胺（IFF）和达卡巴嗪（DTIC）（AID）联合方案具有可接受的毒性且活性显著。20例患者接受了79个疗程的DOX（60 - 75mg/m²），联合或不联合DTIC（900mg/m²），通过72小时持续输注，并逐步增加IFF剂量及使用美司钠进行尿路保护。19例患者可进行毒性评估。骨髓抑制是剂量限制性毒性。每个疗程的最大耐受剂量为DOX 60mg/m²、DTIC 900mg/m²和IFF 7500mg/m²。在分析的79个疗程中，33个（42%）导致白细胞计数低于1000/微升；14个（18%）并发发热和中性粒细胞减少，3个并发败血症。无毒性死亡病例。观察到相对的血小板保护作用，且最低点持续时间较短。与分5天给予大剂量DTIC相比，持续输注DTIC并未显著增加胃肠道毒性。恶心和呕吐通过止吐药得到良好控制。黏膜炎症偶有发生。与我们单独使用IFF的II期研究不同，未观察到中枢神经系统或肾脏毒性。未出现心脏毒性，尽管只有4例患者累积接受的DOX超过450mg/m²。尽管静脉输液管很长一直延伸到腋窝，但仍发生了1次DOX外渗。未观察到严重的组织损伤，这可能是由于所使用的DOX溶液稀释的缘故。18例可评估患者中有8例（44%）出现部分缓解，11例处于或接近II期水平的患者中有6例出现部分缓解。另外2例反应轻微的患者肿瘤持续消退。出现部分缓解前的疗程中位数为4个（范围为1至5个）。反应持续时间的中位数尚未达到（3 +至10 +个月）。1例无法手术切除的原发性肿瘤患者经治疗后已可进行手术切除。对于先前未经治疗的肉瘤患者，应通过一项针对含标准DOX联合方案的随机III期研究进一步评估该方案的活性。
